ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity
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PROVIDER: PRJNA1159196 | ENA |
REPOSITORIES: ENA
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Project description:Alpha-thalassemia X-linked intellectual disability syndrome (ATR-X) is caused by mutations in the ATRX gene, which plays a pivotal role in heterochromatin integrity. In this study, we uncover a novel mechanism by which ATRX influences fate of human neural progenitor cells (hNPCs) through the formation of liquid-liquid phase separation (LLPS)-driven condensates. We discovered that the intrinsically disordered region (IDR) of ATRX is essential for driving LLPS, enabling ATRX to form dynamic condensates within the nucleus. The IDR region can autonomously form phase-separated droplets and recruit co-activators. In addition, formation of these condensates was crucial for the localization of ATRX at super-enhancers (SEs) in hNPCs, directly linking ATRX condensate dynamics to the regulation of gene expression critical for neural differentiation. Disruption of ATRX condensates leads to impaired neuronal differentiation, emphasizing the functional significance of ATRX in human neural development. Our findings provide new insights into the molecular function of ATRX beyond its established roles in chromatin structure, and suggest that LLPS is a key regulatory mechanism through which ATRX supports neurodevelopment. This study opens avenues for further exploration of how dysregulation of ATRX and its phase-separation ability may contribute to the pathogenesis of ATR-X syndrome and related neurodevelopmental disorders.
2025-07-13 | GSE276835 | GEO
Project description:Alpha-thalassemia X-linked intellectual disability syndrome (ATR-X) is caused by mutations in the ATRX gene, which plays a pivotal role in heterochromatin integrity. In this study, we uncover a novel mechanism by which ATRX influences fate of human neural progenitor cells (hNPCs) through the formation of liquid-liquid phase separation (LLPS)-driven condensates. We discovered that the intrinsically disordered region (IDR) of ATRX is essential for driving LLPS, enabling ATRX to form dynamic condensates within the nucleus. The IDR region can autonomously form phase-separated droplets and recruit co-activators. In addition, formation of these condensates was crucial for the localization of ATRX at super-enhancers (SEs) in hNPCs, directly linking ATRX condensate dynamics to the regulation of gene expression critical for neural differentiation. Disruption of ATRX condensates leads to impaired neuronal differentiation, emphasizing the functional significance of ATRX in human neural development. Our findings provide new insights into the molecular function of ATRX beyond its established roles in chromatin structure, and suggest that LLPS is a key regulatory mechanism through which ATRX supports neurodevelopment. This study opens avenues for further exploration of how dysregulation of ATRX and its phase-separation ability may contribute to the pathogenesis of ATR-X syndrome and related neurodevelopmental disorders.
2025-07-13 | GSE276834 | GEO
Project description:ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity (RNA)
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Project description:ATRX Condensates Formed by Liquid-Liquid Phase Separation Regulate Neural Progenitor Cell Identity (ChIP)
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Project description:This SuperSeries is composed of the SubSeries listed below.
2025-07-13 | GSE276836 | GEO
Project description:Bacterial Heterochromatin Formation Through Liquid-Liquid Phase Separation
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Project description:We investigated the role of the nucleolar protein Treacle in organizing and regulating the nucleolus in human cells. Our results support Treacle’s ability to form liquid-like phase condensates through electrostatic interactions among molecules. The formation of these biomolecular condensates is crucial for segregating nucleolar fibrillar centers from the dense fibrillar component and ensuring high levels of rRNA gene transcription and accurate rRNA processing. Both the central and C-terminal domains of Treacle are required to form liquid-like condensates. The initiation of phase separation is attributed to the C-terminal domain. The central domain is characterized by repeated stretches of alternatively charged amino-acid residues and is vital for condensate stability. Overexpression of mutant forms of Treacle that cannot form liquid-like phase condensates compromises the assembly of fibrillar centers, suppressing rRNA gene transcription and disrupting rRNA processing. These mutant forms also fail to recruit DNA topoisomerase II binding protein 1 (TOPBP1), suppressing the DNA damage response in the nucleolus.
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Project description:Muscle morphogenesis is a multi-step program, starting with myoblast fusion, followed by myotube-tendon attachment and sarcomere assembly, with subsequent sarcomere maturation, mitochondrial amplification and specialisation. The correct chronological order of these steps requires precise control of the transcriptional regulators and their effectors. How this regulation is achieved during muscle development is not well understood. In a genome-wide RNAi screen inDrosophila, we identified the BTB-zinc finger protein Tono (CG32121) as a muscle-specific transcriptional regulator.tonomutant flight muscles display severe deficits in mitochondria and sarcomere maturation, resulting in uncontrolled contractile forces causing muscle atrophy during development. Tono protein is expressed during sarcomere maturation and localises in distinct condensates in flight muscle nuclei. Interestingly, internal pressure exerted by the maturing sarcomeres deforms the muscle nuclei into elongated shapes and changes the Tono condensates, suggesting that Tono senses the mechanical status of the muscle cells. Indeed, external mechanical pressure on the muscles triggers rapid liquid-liquid phase separation of Tono utilising its BTB domain. Thus, we propose that Tono senses high mechanical pressure to in turn adapt muscle transcription specifically at the sarcomere maturation stage. Consistently,tonomutant muscles display specific defects in a transcriptional switch that represses early muscle differentiation genes and boosts late ones. We hypothesise that a similar mechano-responsive regulation mechanism may control the activity of related BTB-zinc finger proteins that, if mutated, can result in uncontrolled force production in human muscle.
2024-06-30 | GSE270794 | GEO
Project description:Components of the transcription machinery can undergo liquid-liquid phase separation, but the functional importance of phase-separated condensates in transcriptional control is not well understood. Here we report that disease-causing mutations in several transcription factors (TFs) alter the phase separation capacity of those TFs. We first demonstrate that the Hoxd13 TF, and its intrinsically disordered N-terminus form phase-separated condensates. Expansions of a polyalanine repeat, which cause hereditary synpolydactyly in humans, facilitate phase separation of Hoxd13, and alter the transcriptional program of several cell types in a cell-specific manner in vivo. Disease-associated expansions of aminoacid repeats in intrinsically disordered regions of other TFs were similarly found to alter phase separation. These results suggest that aberrant phase separation of transcriptional regulators may underlie a spectrum of human pathologies. The paper is available at https://doi.org/10.1016/j.cell.2020.04.018
2020-05-07 | GSE128818 | GEO
Project description:MeCP2 (methyl CpG binding protein 2) is a key component of constitutive heterochromatin, which plays important roles in chromosome maintenance and transcriptional silencing. Mutations in MeCP2 cause Rett syndrome (RTT), a postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like symptoms that manifests in girls during early childhood. Heterochromatin, long considered a dense and relatively static structure, is now understood to exhibit properties consistent with a liquid-like condensate. Here we report that MeCP2 is a dynamic component of heterochromatin condensates in cells, is stimulated by DNA to form liquid-like condensates, contains multiple domains that contribute to condensate formation, manifests physicochemical properties that selectively concentrate heterochromatin cofactors compared to components of transcriptionally active condensates, and when altered by RTT-causing mutations is disrupted in its ability to form condensates. We propose that MeCP2 enhances heterochromatin/euchromatin separation through its condensate partitioning properties and that condensate disruption may be a common consequence of RTT patient mutations.
2020-06-23 | GSE139033 | GEO